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\begin{document}

\title{Comment on Halken et al}



\author[1]{Stefano Miceli Sopo}%
\author[2]{Dario Sinatti}%
\author[3]{Francesco Mastellone}%
\author[1]{Giulia Bersani}%
\author[2]{Mariannita Gelsomino}%
\affil[1]{Catholic University}%
\affil[2]{Policlinico Universitario Agostino Gemelli}%
\affil[3]{Fondazione Policlinico Universitario Agostino Gemelli IRCCS}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\textbf{Title:}

Comment on Halken et al

\textbf{Authors} :

Stefano Miceli Sopo \textsuperscript{a}, Dario
Sinatti\textsuperscript{a}, Francesco Mastellone \textsuperscript{b},
Giulia Bersani \textsuperscript{a}, Mariannita Gelsomino
\textsuperscript{b}.

\textbf{Affiliations:}

\textsuperscript{a} Pediatric Allergy Unit, Pediatrics Section,
Department of Life Sciences and Public Health, Policlinico Gemelli
Universitary Foundation IRCCS, Catholic University of Sacre Hearth, Rome
00168, Italy.

\textsuperscript{b} Post-Graduate School of Pediatrics, Department of
Life Sciences and Public Health, Policlinico Gemelli Universitary
Foundation IRCCS, Catholic University of Sacre Hearth, Rome 00168,
Italy.

\textbf{Correspondence} :

Stefano Miceli Sopo

Pediatric Allergy Unit, Pediatrics Section, Department of Life Sciences
and Public Health, Policlinico Gemelli University Foundation IRCCS,
Catholic University of Sacred Heart, Rome, Italy.

Email: stefano.micelisopo@unicatt.it

\textbf{Word count} : 503

\textbf{Number of tables} : 0

\textbf{Numbers of figures} : 0

\textbf{Material in the electronic repository} : not applicable

\textbf{Ethical approval and trial registration} : not applicable.

\textbf{Consent for publication} : not applicable.

\textbf{Data sharing and data accessibility} : not applicable.

\textbf{Conflict of interests} : the authors declare that they have no
conflict of interests to disclose in relation to this paper.

\textbf{Financial support} : this research did not receive any specific
grant from funding agencies in the public, commercial, or non-profit
sectors.

\textbf{Acknowledgements} : not applicable.

\textbf{Abstract} : not applicable.

\textbf{Keywords} : complementary feeding, egg allergy, food allergy
prevention, pediatrics

\textbf{Key Messages} : not applicable.

\textbf{Main text:}

\emph{To the Editor}

We read with great interest the European Academy of Allergy and Clinical
Immunology (EAACI) guideline on prevention of food allergy (FA) (1). In
particular, recommendation 3.1.2 states: ``The EAACI Task Force suggests
introducing well-cooked hen's egg, but not raw egg or uncooked
pasteurized egg, into the infant diet as part of complementary feeding
to prevent egg allergy in infants.'' The authors declare in advance that
only Intention-To-Treat (ITT) analyses were considered and they cite, in
support of the aforementioned recommendation, four studies (2-5).

However, according to the ITT analysis, the first two studies (2, 3)
find no evidence that consumption of hen's egg prevents hen's egg
allergy. The third study (4) reports an efficacy in this regard, but the
authors: a) enrolled children with eczema, therefore a category at
increased risk of developing FA; b) have associated aggressive eczema
treatment, and it is not possible to establish the weight of one and the
other treatment on the final outcome; c) excluded from the final
analysis of the data about 18\% of randomized patients, and it is
difficult for statistical significance to be maintained if the
worst-case scenario analysis were applied. Moreover, we consider
technically difficult for a parent to be able to weigh 50 mg of cooked
egg powder to be given to their child, as Natsume et al (4) suggest. At
the end, the authors (4) evaluated the effectiveness of their preventive
strategy with an oral food challenge with 7 g of heated whole-egg
powder, and therefore the study in question cannot tell us anything
about the possible effectiveness in the prevention of allergy to raw or
undercooked egg. The fourth study (5) cited by the EAACI Task Force (1),
is based on a subgroup analysis that did not benefit from a specific
randomization. The previously unplanned subgroup analysis, in the
absence of specific randomization, is well used for formulating
hypotheses to be tested with a specifically planned study, but is less
adequate to support a recommendation contained in a guideline.

In short, it seems to us that recommendation 3.1.2 (1) cannot be issued.
Moreover, no times and doses are indicated to start the possible
administration of well-cooked egg, and even this definition seems a bit
vague (``well cooked'' means baked? Or hard boiled?). Contrary to our
objection, other position papers of very authoritative scientific
societies (6-10) substantially agree with recommendation 3.1.2 of the
EAACI Task Force (1). However, even in these documents, the supporting
evidence does not seem sufficient. In particular, table IV by Fleischer
et al (7), which effectively summarizes the evidence available until
2021 on this topic, is very clear in this regard. Examining it, in fact,
it is clear that we do not have the availability of methodologically
valid studies that allow us to argue that the introduction of cooked egg
during the complementary feeding, as the only intervention, reduces the
likelihood of hen's egg allergy, neither in infants at increased risk of
developing FA nor in those at normal risk.

Stefano Miceli Sopo \textsuperscript{a} Prof

Dario Sinatti \textsuperscript{a} MD

Francesco Mastellone \textsuperscript{b} MD

Giulia Bersani \textsuperscript{a} MD

Mariannita Gelsomino \textsuperscript{b} MD.

\textsuperscript{a} Pediatric Allergy Unit, Pediatrics Section,
Department of Life Sciences and Public Health, Policlinico Gemelli
Universitary Foundation IRCCS, Catholic University of Sacre Hearth, Rome
00168, Italy.

\textsuperscript{b} Post-Graduate School of Pediatrics, Department of
Life Sciences and Public Health, Policlinico Gemelli Universitary
Foundation IRCCS, Catholic University of Sacre Hearth, Rome 00168,
Italy.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Halken S, Muraro A, de Silva D, et al. EAACI guideline: Preventing the
  development of food allergy in infants and young children (2020
  update). Pediatr Allergy Immunol. 2021;32(5):843-858.
\item
  Perkin MR, Logan K, Tseng A, et al. Randomized trial of introduction
  of allergenic foods in breast-fed infants. N Engl J Med.
  2016;374(18):1733-1743.
\item
  Bellach J, Schwarz V, Ahrens B, et al. Randomized placebo-controlled
  trial of hen's egg consumption for primary prevention in infants. J
  Allergy Clin Immunol. 2017;139(5):1591-1599.
\item
  Natsume O, Kabashima S, Nakazato J, et al. Two-step egg introduction
  for prevention of egg allergy in high-risk infants with eczema
  (PETIT): a randomised, double-blind, placebo-controlled trial. Lancet.
  2017;389(10066):276-286.
\item
  Perkin MR, Logan K, Bahnson HT, et al. Efficacy of the enquiring About
  Tolerance (EAT) study among infants at high risk of developing food
  allergy. J Allergy Clin Immunol. 2019;144(6):1606-1614.
\item
  Leech SC, Ewan PW, Skypala IJ, et al. BSACI 2021 guideline for the
  management of egg allergy. Clin Exp Allergy. 2021;51(10):1262-1278.
\item
  Fleischer DM, Chan ES, Venter C, et al. A Consensus Approach to the
  Primary Prevention of Food Allergy Through Nutrition: Guidance from
  the American Academy of Allergy, Asthma, and Immunology; American
  College of Allergy, Asthma, and Immunology; and the Canadian Society
  for Allergy and Clinical Immunology. J Allergy Clin Immunol Pract.
  2021;9(1):22-43.e4.
\item
  Joshi PA, Smith J, Vale S, et al. The Australasian Society of Clinical
  Immunology and Allergy infant feeding for allergy prevention
  guidelines. Med J Aust. 2019; 210(2): 89-93.
\item
  Worm M, Reese I, Ballmer-Weber B, et al. Update of the S2k guideline
  on the management of IgE-mediated food allergies. Allergol Select.
  2021; 5: 195-243.
\item
  Sabouraud-Leclerc D, Bradatan E, Moraly T, et al. Primary prevention
  of food allergy in 2021: Update and proposals of French-speaking
  pediatric allergists. Arch Pediatr. 2021: S0929-693X(21)00241-4.
\end{enumerate}

\textbf{Tables} : None

\textbf{Figures} : None

\textbf{Appendices} : Not applicable.

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